Caveolin-1 mediates cellular distribution of HER2 and affects trastuzumab binding and therapeutic efficacy Journal Article

Authors: Pereira, P. M. R.; Sharma, S. K.; Carter, L. M.; Edwards, K. J.; Pourat, J.; Ragupathi, A.; Janjigian, Y. Y.; Durack, J. C.; Lewis, J. S.
Article Title: Caveolin-1 mediates cellular distribution of HER2 and affects trastuzumab binding and therapeutic efficacy
Abstract: Human epidermal growth factor receptor 2 (HER2) gene amplification and/or protein overexpression in tumors is a prerequisite for initiation of trastuzumab therapy. Although HER2 is a cell membrane receptor, differential rates of endocytosis and recycling engender a dynamic surface pool of HER2. Since trastuzumab must bind to the extracellular domain of HER2, a depressed HER2 surface pool hinders binding. Using in vivo biological models and cultures of fresh human tumors, we find that the caveolin-1 (CAV1) protein is involved in HER2 cell membrane dynamics within the context of receptor endocytosis. The translational significance of this finding is highlighted by our observation that temporal CAV1 depletion with lovastatin increases HER2 half-life and availability at the cell membrane resulting in improved trastuzumab binding and therapy against HER2-positive tumors. These data show the important role that CAV1 plays in the effectiveness of trastuzumab to target HER2-positive tumors. © 2018, The Author(s).
Keywords: controlled study; human tissue; human cell; drug efficacy; nonhuman; mouse; animal tissue; gene; gene expression; protein depletion; epidermal growth factor receptor 2; animal experiment; animal model; protein; bladder cancer; amplification; cell membrane; cellular distribution; tumor; trastuzumab; endocytosis; drug binding; cell; chemical binding; membrane; caveolin 1; cell component; human; female; article; mcf-7 cell line; mda-mb-231 cell line; bladder tissue; bt-474 cell line; kato iii cell line; nci-n87 cell line; sk-br-3 cell line
Journal Title: Nature Communications
Volume: 9
ISSN: 2041-1723
Publisher: Nature Publishing Group  
Date Published: 2018-12-03
Start Page: 5137
Language: English
DOI: 10.1038/s41467-018-07608-w
PROVIDER: scopus c7 - 5137 c2 - 30510281
PMCID: PMC6277446
PUBMED: 30510281
Notes: Nat. Commun. -- Export Date: 2 January 2019 -- Article -- Source: Scopus C7 - 5137 C2 - 30510281
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MSK Authors
  1. Yelena Yuriy Janjigian
    133 Janjigian
  2. Jason S Lewis
    239 Lewis
  3. Jeremy Charles Durack
    82 Durack
  4. Sai Kiran   Sharma
    11 Sharma
  5. Kimberly Joanna Edwards
    10 Edwards
  6. Jacob   Pourat
    6 Pourat
  7. Lukas M Carter
    6 Carter